Compositions of essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof

ABSTRACT

The present disclosure relates to: a) a crystalline composition of essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) pharmaceutical compositions comprising the crystalline composition of essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and, optionally, a pharmaceutically acceptable carrier; and c) methods of treating a tumor, a cancer, or a Rasopathy disorder by administering the crystalline composition of essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide to a subject in need thereof.

FIELD OF THE INVENTION

The present disclosure relates to: a) a crystalline composition that isessentially pure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;b) pharmaceutical compositions comprising the crystalline compositionthat is essentially pure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,and, optionally, a pharmaceutically acceptable carrier; and c) methodsof treating a tumor, a cancer, or a Rasopathy disorder by administeringthe crystalline composition that is essentially pure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideto a subject in need thereof.

BACKGROUND

N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide(“mirdametinib”, or “PD-0325901”) is a small molecule drug which hasbeen designed to inhibit mitogen-activated protein kinase kinase 1(“MEK1”) and mitogen-activated protein kinase kinase 2 (“MEK2”). MEK1and MEK2 are proteins that play key roles in the mitogen-activatedprotein kinase (“MAPK”) signaling pathway. The MAPK pathway is criticalfor cell survival and proliferation, and overactivation of this pathwayhas been shown to lead to tumor development and growth. Mirdametinib isa highly potent and specific allosteric non-ATP-competitive inhibitor ofMEK1 and MEK2. By virtue of its mechanism of action, mirdametinib leadsto significantly inhibited phosphorylation of the extracellularregulated MAP kinases ERK1 and ERK2, thereby leading to impaired growthof tumor cells both in vitro and in vivo. In addition, evidenceindicates that inflammatory cytokine-induced increases in MEK/ERKactivity contribute to the inflammation, pain, and tissue destructionassociated with rheumatoid arthritis and other inflammatory diseases.

Crystal forms ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidehave been described previously. WO2002/006213 describes crystallineForms I and II. U.S. Pat. No. 7,060,856 (“the '856 patent”) describes amethod of producing Form IV. The '856 patent indicates that the materialproduced by this method was greater than 90% Form IV (The '856 patent,Example 1). The '856 patent also states that the differential scanningcalorimetry (“DSC”) of the material produced shows an onset of meltingat 110° C., as well as a small peak with an onset at 117° C., consistentwith the material being a mixture of two forms.

WO 2006/134469 (“the '469 PCT publication”) also describes a method ofsynthesizingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.The '469 PCT publication reports the method yields a product conformingto the polymorphic Form IV disclosed in U.S. patent application Ser. No.10/969,681 which issued as the '856 patent.

Compositions containing more than one polymorphic form are generallyundesirable because of the potential of interconversion of onepolymorphic form to another. Polymorphic interconversion can lead todifferences in the effective dose or physical properties affectingprocessability of a drug, caused by differences in solubility orbioavailability. Thus, there is a need for a composition containingessentially pure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,for use in treatment of a tumor, a cancer, or a Rasopathy disorder.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is a X-ray powder diffraction pattern (“XRPD”) corresponding toessentially pure crystalline Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

FIG. 1B is a thermogravimetric analysis thermogram (“TGA”) and adifferential scanning calorimetry thermogram (“DSC”) corresponding toessentially pure crystalline Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

FIG. 2 is an XRPD corresponding to a batch of essentially pure Form IVofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideas initially prepared and an XRPD of a known reference standard of FormIV.

FIG. 3A is an XRPD corresponding to essentially pure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideafter storage for 68 months after production at 25° C. and 65% relativehumidity.

FIG. 3B is an XRPD corresponding to essentially pure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideafter storage for 140 months after production at 25° C. and 65% relativehumidity.

BRIEF SUMMARY OF THE INVENTION

The present disclosure features useful compositions and methods to treatdisorders whereby aberrant MEK1 or MEK2 activity is implicated, e.g., acancer, a tumor, or a Rasopathy disorder, such as neurofibromatosis type1, in a subject in need thereof.

In some aspects, the present disclosure is directed to a crystallinecomposition of essentially pure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

In some aspects, the crystalline composition of essentially pureN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedoes not contain any amount of Form I or Form II detectable by XRPDand/or DSC.

In some aspects, the crystalline composition exhibits an XRPD patternand/or DSC profile which is substantially unchanged after storage for 3months at standard warehouse conditions (15° C.-25° C. and ≤65% relativehumidity). In some aspects, the crystalline composition exhibits an XRPDpattern and/or DSC profile which is substantially unchanged afterstorage for 6 months at standard warehouse conditions (15° C.-25° C. and≤65% relative humidity). In some aspects, the crystalline compositionexhibits an XRPD pattern and/or DSC profile which is substantiallyunchanged after storage for 1 year at standard warehouse conditions (15°C.-25° C. and ≤65% relative humidity). In some aspects, the crystallinecomposition exhibits an XRPD pattern and/or DSC profile which issubstantially unchanged after storage for 5 years at standard warehouseconditions (15° C.-25° C. and ≤65% relative humidity). In some aspects,the crystalline composition exhibits an XRPD pattern and/or DSC profilewhich is substantially unchanged after storage for 68 months at standardwarehouse conditions (15° C.-25° C. and ≤65% relative humidity). In someaspects, the crystalline composition exhibits an XRPD pattern and/or DSCprofile which is substantially unchanged after storage for ≥140 monthsat standard warehouse conditions (15° C.-25° C. and ≤65% relativehumidity). In some aspects, the crystalline composition exhibits an XRPDpattern and/or DSC profile which is substantially unchanged afterstorage for ≥14 years at standard warehouse conditions (15° C.-25° C.and ≤65% relative humidity).

In some aspects, the XRPD pattern is generated using a PANALYTICAL®X'Pert Pro diffractometer using Ni-filtered Cu Kα (45 kV/40 mA)radiation and a step size of 0.03° 2θ with a X'CELERATOR® Real TimeMulti-Strip detector, configured (a) on the incidental beam side asfollows: variable divergence slits (10 mm irradiated length), 0.04 radSoller slits, fixed anti-scatter slit (0.50°), and 10 mm beam mask, and(b) on the diffracted beam side as follows: variable anti-scatter slit(10 mm observed length) and 0.04 rad Soller slit or a BRUKER® D8®ADVANCE™ system using Cu Kα (40 kV/40 mA) radiation and a step size of0.03° 2θ with a LYNXEYE™ detector, configured (a) on the incidental beamside as follows: Goebel mirror, mirror exit slit (0.2 mm), 2.5° Sollerslit, beam knife, and (b) on the diffracted beam side as follows:anti-scatter slit (8 mm) and 2.5° Soller slit; wherein samples aremounted flat on zero-background Si wafers. In some aspects, the DSCpattern is generated using a TA Instruments Q100 or Q2000 differentialscanning calorimeter at a rate of temperature increase of about 15°C./min.

In some aspects, the crystalline composition contains ≤0.2% of dimericimpurity PF-00191189

In some aspects, the crystalline composition contains about 0.05% toabout 0.19% by weight of dimeric impurity PF-00191189. In some aspects,the crystalline composition contains no detectable amount of dimericimpurity PF-00191189.

In some aspects, the present disclosure provides a pharmaceuticalcomposition comprising a crystalline composition described herein and apharmaceutically acceptable carrier. In some aspects, the pharmaceuticalcomposition is for oral administration. In some aspects, thepharmaceutical composition is a solid dosage form. In some aspects, thepharmaceutical composition is a tablet or capsule. In some aspects, thepharmaceutical composition is a tablet.

In some aspects, the pharmaceutical composition is a capsule. In someaspects, the capsule comprises about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.25wt/wt % to about 1.5 wt/wt % of the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d)about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and agelatin capsule which encapsulates components a-d. In some aspects, thecapsule comprises about 2 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.25wt/wt % to about 1.5 wt/wt % of the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d)about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and (e)a gelatin capsule which encapsulates components a-d. In some aspects,the capsule comprises about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt % of the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; and(d) a gelatin capsule which encapsulates components a-c.

In some aspects, at least one of the diluents is selected from the groupconsisting of microcrystalline cellulose, lactose, mannitol, starch, anddibasic calcium phosphate. In some aspects, at least one of the diluentsis microcrystalline cellulose.

In some aspects, at least one of the disintegrants is selected from thegroup consisting of croscarmellose sodium, sodium starch glycolate,crospovidone, and alginic acid. In some aspects, at least one of thedisintegrants is croscarmellose sodium.

In some aspects, at least one of the lubricants is selected from thegroup consisting of magnesium stearate, sodium stearyl fumarate,glycerol dibehenate, and talc. In some aspects, at least one of thelubricants is magnesium stearate.

In some aspects, the present disclosure provides a method of treating acancer, a tumor, or a Rasopathy disorder comprising administering to asubject in need of such treatment a pharmaceutical composition describedherein.

In some aspects, the tumor is a neurofibroma. In some aspects, the tumoris a neurofibroma associated with Neurofibromatosis Type 1. In someaspects, the tumor is selected from the group consisting of cutaneousneurofibroma, plexiform neurofibroma, optic pathway glioma, low gradeglioma, high grade glioma, or malignant peripheral nerve sheath tumor.In some aspects, the tumor is plexiform neurofibroma.

In some aspects, the subject has been diagnosed with a Rasopathydisorder selected from the group consisting of neurofibromatosis type 1,neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costellosyndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome withmultiple lentigines.

In some aspects, the cancer is selected from the group consisting ofskin cancer, malignant peripheral nerve sheath cancer, leukemia,lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovariancancer, renal cancer, colorectal cancer, thyroid cancer,cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer,sarcoma, bladder cancer, head and neck cancer, endometrial cancer,esophageal cancer, adenoid cystic carcinoma, gallbladder cancer,prostate cancer, oral cancer, cervical cancer, pancreatic cancer,melanoma, hepatocellular cancer, biliary tract cancer, and serouscarcinoma of the peritoneum. In some aspects, the leukemia is selectedfrom the group consisting of acute lymphocytic leukemia, acutemyelogenous leukemia, chronic lymphocytic leukemia, and chronicmyelogenous leukemia. In some aspects, the lymphoma is selected from thegroup consisting of B-cell lymphoma, T-cell lymphoma, Burkitt'slymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinalB cell lymphoma, small lymphocytic lymphoma, and Waldenstrommacroglobulinemia. In some aspects, the lung cancer is selected from thegroup consisting of lung adenocarcinoma, squamous non-small cell lungcancer, non-squamous non-small cell lung cancer, and small cell lungcancer.

In some aspects, the subject bears a mutation or other aberration in oneor more genes for which the mutation or other aberration causes a gainor loss of function characteristic of certain cancers, wherein themutation or other aberration in one or more genes is a mutation or otheraberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1,MAP2K4, NF1, or NF2.

In some aspects, an individual dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered as more than one capsule or tablet.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 20 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 10 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 8 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 6 mg.

In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis about 0.1 mg to about 20 mg. In some aspects, the total daily dose oftheN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis about 2 mg. In some aspects, the total daily dose ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis about 4 mg. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis about 6 mg. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis about 8 mg. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered about 20 mg.

In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily. In some aspects, the total daily doseof theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.1 mg to about 10 mgeach. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 1 mg each. In someaspects, the total daily dose ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 2 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 3 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 4 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 10 mg each.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 days inwhich the total daily dose is administered; and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered. In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 consecutivedays in which the total daily dose is administered; followed by (b) 7consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 days in which the total daily dose isadministered and (ii) 2 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered. In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 consecutive days in which the total dailydose is administered and (ii) 2 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;followed by (b) 7 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

In some aspects, the 28-day dosing cycle is repeated up to a total of 24consecutive 28-day dosing cycles.

In some aspects, the present disclosure provides use of a pharmaceuticalcomposition described herein for the manufacture of a medicament fortreating a tumor, a cancer, or a Rasopathy disorder.

Method of Manufacturing a Pharmaceutical Composition

In some aspects, the present disclosure provides a method ofmanufacturing a pharmaceutical composition, the method comprisingforming a pharmaceutical composition described herein.

Definitions

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well-known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs.

In this specification and the appended claims, the singular forms “a,”“an” and “the” include plural referents unless the context clearlydictates otherwise. The terms “a” (or “an”), as well as the terms “oneor more,” and “at least one” can be used interchangeably herein. Incertain aspects, the term “a” or “an” means “single.” In other aspects,the term “a” or “an” includes “two or more” or “multiple.”

Furthermore, “and/or” where used herein is to be taken as specificdisclosure of each of the two specified features or components with orwithout the other. Thus, the term “and/or” as used in a phrase such as“A and/or B” herein is intended to include “A and B,” “A or B,” “A”(alone), and “B” (alone). Likewise, the term “and/or” as used in aphrase such as “A, B, and/or C” is intended to encompass each of thefollowing aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; Aand C; A and B; B and C; A (alone); B (alone); and C (alone).

The terms “mirdametinib” and “PD-0325901” refer to the single enantiomerN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat,or mouse. The terms “subject” and “patient” are used interchangeablyherein in reference, for example, to a mammalian subject, such as ahuman subject.

As used herein, the terms “treat,” “treated,” and “treating” mean boththerapeutic treatment and prophylactic or preventative measures whereinthe object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder, or disease, or obtain beneficial ordesired clinical results. Thus, those in need of treatment include thosealready diagnosed with or suspected of having the disorder. Beneficialor desired clinical results include, but are not limited to, alleviationof symptoms; diminishment of the extent of a condition, disorder, ordisease; stabilized (i.e., not worsening) state of condition, disorder,or disease; delay in onset or slowing of condition, disorder, or diseaseprogression; amelioration of the condition, disorder, or disease stateor remission (whether partial or total), whether detectable orundetectable; an amelioration of at least one measurable physicalparameter, not necessarily discernible by the patient; or enhancement orimprovement of condition, disorder, or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment. The term “therapeuticallyeffective amount” is meant to include the amount of a compound that,when administered, is sufficient to prevent development of, or alleviateto some extent, one or more of the symptoms of a disorder, disease, orcondition being treated. The term “therapeutically effective amount”also refers to the amount of a compound that is sufficient to elicit thebiological or medical response of a cell, tissue, system, animal, orhuman, which is being sought by a researcher, veterinarian, medicaldoctor, or clinician.

In certain aspects, a subject is successfully “treated” for a tumor,according to the methods described herein if the patient shows one ormore of the following: a reduction in the size of the tumor; relief ofone or more symptoms associated with the specific tumor; a reduction inthe volume of the tumor; improvement in quality of life; increasedprogression-free survival (PFS), disease-free survival (DFS), overallsurvival (OS), metastasis-free survival (MFS), complete response (CR),minimal residual disease (MRD), partial response (PR), stable disease(SD), a decrease in progressive disease (PD), an increased time toprogression (TTP), or any combination thereof. In some aspects,nationally or internationally accepted standards of treatment outcomesin a given tumor can be used to determine whether an effective amount ofmirdametinib meets any of these particular endpoints (e.g., CR, PFS,PR).

In certain aspects, a subject is successfully “treated” for cancer,e.g., lung cancer or ovarian cancer, according to the methods describedherein if the patient shows one or more of the following: a reduction inthe number of or complete absence of cancer cells; relief of one or moresymptoms associated with the specific cancer; reduced morbidity andmortality; improvement in quality of life; increased progression-freesurvival (PFS), disease-free survival (DFS), overall survival (OS),metastasis-free survival (MFS), complete response (CR), minimal residualdisease (MRD), partial response (PR), stable disease (SD), a decrease inprogressive disease (PD), an increased time to progression (TTP), or anycombination thereof. In some aspects, nationally or internationallyaccepted standards of treatment outcomes in a given cancer can be usedto determine whether an effective amount of mirdametinib meets any ofthese particular endpoints (e.g., CR, PFS, PR).

The terms “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refer to a pharmaceuticallyacceptable material, composition, or vehicle, such as a liquid or solidexcipient, solvent, or encapsulating material. In one aspect, eachcomponent is “pharmaceutically acceptable” in the sense of beingcompatible with the other ingredients of a pharmaceutical formulation,and suitable for use in contact with the tissue or organ of humans andanimals without excessive toxicity, irritation, allergic response,immunogenicity, or other problems or complications, commensurate with areasonable benefit/risk ratio. See Remington: The Science and Practiceof Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia,Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe etal., Eds., The Pharmaceutical Press and the American PharmaceuticalAssociation: 2005; and Handbook of Pharmaceutical Additives, 3rdEdition, Ash and Ash Eds., Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC PressLLC: Boca Raton, Fla., 2004 (incorporated herein by reference).Excipients can include, for example: antiadherents, antioxidants,binders, coatings, compression aids, disintegrants, dyes (colors),emollients, emulsifiers, fillers (diluents), film formers or coatings,flavors, fragrances, glidants (flow enhancers), lubricants,preservatives, printing inks, sorbents, suspensing or dispersing agents,sweeteners, and waters of hydration. Exemplary excipients include, butare not limited to: butylated hydroxytoluene (BHT), calcium carbonate,calcium phosphate (dibasic), calcium stearate, calcium sulfate,croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid,crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate,maltitol, mannitol, methionine, methylcellulose, methyl paraben,microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone,povidone, pregelatinized starch, propyl paraben, retinyl palmitate,shellac, silicon dioxide, sodium carboxymethyl cellulose, sodiumcitrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid,sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, andxylitol.

The term “pharmaceutical composition,” as used herein, represents acomposition containing a compound described herein formulated with apharmaceutically acceptable excipient, and can be manufactured or soldwith the approval of a governmental regulatory agency as part of atherapeutic regimen for the treatment of disease in a mammal.Pharmaceutical compositions can be formulated, for example, for oraladministration in unit dosage form (e.g., a tablet, capsule, caplet,gelcap, or syrup).

The term “about” or “approximately” means within a range of anacceptable error for a particular value as determined by one of ordinaryskill in the art, which depends in part on how the value is measured ordetermined. In some aspects, the term “about” or “approximately” meanswithin 1, 2, 3, or 4 standard deviations. In some aspects, the term“about” or “approximately” means a quantity, level, value, number,frequency, percentage, dimension, size, amount, weight or length thatvaries by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%to a reference quantity, level, value, number, frequency, percentage,dimension, size, amount, weight or length.

As used herein, the term “administration” refers to the administrationof a composition (e.g., a compound or a preparation that includes acompound as described herein) to a subject or system. Administration toan animal subject (e.g., to a human) can be by any appropriate route,such as one described herein.

The term “crystalline,” as used herein, refers to a solid-state formwhich consists of orderly arrangement of structural units. Differentcrystalline forms of the same compound, or a salt, hydrate, or solvatethereof, arise from different packing of the molecules in thesolid-state, which results in different crystal symmetries and/or unitcell parameter. Different crystalline forms usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility. See, e.g., Remington's Pharmaceutical Sciences, 18thed., Mack Publishing, Easton Pa., 173 (1990); The United StatesPharmacopeia, 23rd ed., 1843-1844 (1995) (incorporated herein byreference).

Crystalline forms are commonly characterized by X-ray powder diffraction(XRPD). An XRPD pattern of reflections (peaks, typically expressed indegrees 2-theta) is commonly considered a fingerprint of a particularcrystalline form. The relative intensities of the XRPD peaks can widelyvary depending on, inter alia, the sample preparation technique, crystalsize distribution, filters, the sample mounting procedure, and theparticular instrument employed. In some instances, new peaks may beobserved or existing peaks may disappear, depending on the type ofinstrument or the settings. In some instances, any particular peak in anXRPD pattern may appear as a singlet, doublet, triplet, quartet, ormultiplet, depending on the type of instrument or the settings, thesensitivity of the instrument, measuring conditions, and/or purity ofthe crystalline form. In some instances, any particular peak in an XRPDmay appear in a symmetric shape or in an asymmetric shape, e.g., havinga shoulder. Moreover, instrument variation and other factors can affectthe 2-theta values. A skilled artisan understanding these variations iscapable of discriminating or ascertaining the defining features orcharacteristics of a particular crystal form using XRPD, as well asusing other known physicochemical techniques.

The term “anhydrate” as applied to a compound refers to a crystallineform wherein the compound contains no structural water within thecrystal lattice.

As used herein, the term “essentially pure” with respect to Form IVmeans that the composition comprising Form IV contains no detectableamount of another polymorphic form (e.g., Form I or Form II), asdetermined by observing no detectable differences in an XRPD and/or DSCpattern between a single Form IV crystal and the crystalline compositionofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.However, “essentially pure” Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide”can include impurities, such as, but not limited to, synthetic reactantsor by-products generated during the chemical synthesis.

As used herein, the term “aberration” as applied to a gene refers to amutation, chromosomal loss or fusion, epigenetic chemical modification,or other event which alters the sequence, level of expression, orprocessed mRNA sequence associated with a gene relative to the sequence,level of expression, or processed mRNA sequence associated with thewild-type gene.

It is understood that wherever aspects are described herein with thelanguage “comprising,” otherwise analogous aspects described in terms of“consisting of” and/or “consisting essentially of” are also provided.

The details of one or more aspects are set forth in the descriptionbelow. Other features, objects, and advantages will be apparent from thedescription and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

Essentially pure Form IV, compositions that are essentially pure FormIV, and methods to treat a patient in need of a therapeutic comprisingadministration of essentially pure Form IV are described herein.

Crystalline Composition

The present disclosure relates to an essentially pure crystallinecomposition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.As with all pharmaceutical compounds and compositions, the chemical andphysical properties ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideare important in its commercial development. These properties include,but are not limited to: (1) packing properties such as molar volume,bulk density and hygroscopicity, (2) thermodynamic properties such asmelting temperature, vapor pressure and solubility, (3) kineticproperties such as dissolution rate and stability (including stabilityat ambient conditions, especially to moisture and under storageconditions), (4) surface properties such as surface area, wettability,interfacial tension and shape, (5) mechanical properties such ashardness, tensile strength, compactibility, handling, flow and blend;and (6) filtration properties. These properties can affect, for example,the processing and storage of the compound and pharmaceuticalcompositions comprising the compound.

A crystalline form ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidethat improves upon one or more of these properties relative to othercrystalline forms of the compound is desirable. Isolatingpharmaceutically acceptable crystalline forms of the compound that canbe manufactured and formulated on a commercial scale can be a challenge.

In some aspects, the present disclosure is directed to essentially pureForm IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

In some aspects, the crystalline composition is stable, as demonstratedby a substantially unchanged XRPD pattern and/or DSC profile over time.In some aspects, the crystalline composition exhibits an XRPD patternand/or DSC profile which is substantially unchanged after storage for 1month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8months, 9 months, 10 months, 1 year, 2 years, 3 years, 4 years, 5 years,68 months, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 140months, 12 years, 13 years, 14 years, or 15 years at standard warehouseconditions (15° C.-25° C. and ≤65% relative humidity). In some aspects,the crystalline composition exhibits an XRPD pattern and/or DSC profilewhich is substantially unchanged after storage for 3 months at standardwarehouse conditions (15° C.-25° C. and ≤65% relative humidity). In someaspects, the crystalline composition exhibits an XRPD pattern and/or DSCprofile which is substantially unchanged after storage for 6 months atstandard warehouse conditions (15° C.-25° C. and ≤65% relativehumidity). In some aspects, the crystalline composition exhibits an XRPDpattern and/or DSC profile which is substantially unchanged afterstorage for 1 year at standard warehouse conditions (15° C.-25° C. and≤65% relative humidity). In some aspects, the crystalline compositionexhibits an XRPD pattern and/or DSC profile which is substantiallyunchanged after storage for 5 years at standard warehouse conditions(15° C.-25° C. and ≤65% relative humidity). In some aspects, thecrystalline composition exhibits an XRPD pattern and/or DSC profilewhich is substantially unchanged after storage for 68 months at standardwarehouse conditions (15° C.-25° C. and ≤65% relative humidity). In someaspects, the crystalline composition exhibits an XRPD pattern and/or DSCprofile which is substantially unchanged after storage for ≥140 monthsat standard warehouse conditions (15° C.-25° C. and ≤65% relativehumidity). In some aspects, the crystalline composition exhibits an XRPDpattern and/or DSC profile which is substantially unchanged afterstorage for ≥14 years at standard warehouse conditions (15° C.-25° C.and ≤65% relative humidity).

In some aspects, the XRPD pattern is generated using a PANALYTICAL®X'Pert Pro diffractometer using Ni-filtered Cu Kα (45 kV/40 mA)radiation and a step size of 0.03 2θ with a X'CELERATOR® Real TimeMulti-Strip detector, configured (a) on the incidental beam side asfollows: variable divergence slits (10 mm irradiated length), 0.04 radSoller slits, fixed anti-scatter slit (0.50°), and 10 mm beam mask, and(b) on the diffracted beam side as follows: variable anti-scatter slit(10 mm observed length) and 0.04 rad Soller slit or a BRUKER® D8®ADVANCE™ system using Cu Kα (40 kV/40 mA) radiation and a step size of0.03° 2θ with a LYNXEYE™ detector, configured (a) on the incidental beamside as follows: Goebel mirror, mirror exit slit (0.2 mm), 2.5° Sollerslit, beam knife, and (b) on the diffracted beam side as follows:anti-scatter slit (8 mm) and 2.5° Soller slit; wherein samples aremounted flat on zero-background Si wafers. In some aspects, the DSCpattern is generated using a TA Instruments Q100 or Q2000 differentialscanning calorimeter at a rate of temperature increase of about 15°C./min.

In some aspects, the crystalline composition contains ≤0.2% of dimericimpurity PF-00191189

In some aspects, the crystalline composition contains about 0.05% toabout 0.19% by weight of dimeric impurity PF-00191189. In some aspects,the crystalline composition contains about 0.05% to about 0.15% byweight of dimeric impurity PF-00191189. In some aspects, the crystallinecomposition contains about 0.05% to about 0.10% by weight of dimericimpurity PF-00191189. In some aspects, the crystalline compositioncontains no detectable amount of dimeric impurity PF-00191189.

In some aspects, the amount of dimeric impurity PF-00191189 isdetermined using High Performance Liquid Chromatography (“HPLC”). Insome aspects, reversed-phase liquid chromatography using an ultravioletdetector at 275 nm is used.

In some aspects, the crystalline composition exhibits a DSC profilewhich does not have an endothermic event with onset at about 117° C.

Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis characterized by an XRPD pattern substantially as shown in FIG. 1A, aTGA profile substantially as shown in FIG. 1B; and/or a DSC profilesubstantially as shown in FIG. 1B.

Pharmaceutical Composition

In some aspects, the present disclosure provides a pharmaceuticalcomposition comprising a crystalline composition described herein and apharmaceutically acceptable carrier. In some aspects, the pharmaceuticalcomposition is for oral administration. In some aspects, thepharmaceutical composition is a tablet or capsule. In some aspects, thepharmaceutical composition is a tablet. In some aspects, thepharmaceutical composition is a capsule.

In some aspects, the pharmaceutical composition comprises about 0.1 mgto about 10 mg of the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 0.1 mg,about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg,about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg,about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg,about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, orabout 10 mg of the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 2 mg ofthe crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 3 mg ofthe crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 4 mg ofthe crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.In some aspects, the pharmaceutical composition comprises about 5 mg ofthe crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

In some aspects, the pharmaceutical composition comprises about 0.25wt/wt % to about 7 wt/wt % of the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein. In some aspects, the pharmaceutical compositioncomprises about 0.25 wt/wt %, about 0.3 wt/wt %, about 0.4 wt/wt %,about 0.5 wt/wt %, about 0.6 wt/wt %, about 0.7 wt/wt %, about 0.8 wt/wt%, about 0.9 wt/wt %, about 1 wt/wt %, about 1.1 wt/wt %, about 1.2wt/wt %, about 1.3 wt/wt %, about 1.4 wt/wt %, about 1.5 wt/wt %, about1.6 wt/wt %, about 1.7 wt/wt %, about 1.8 wt/wt %, about 1.9 wt/wt %,about 2 wt/wt %, about 2.1 wt/wt %, about 2.2 wt/wt %, about 2.3 wt/wt%, about 2.4 wt/wt %, about 2.5 wt/wt %, about 2.6 wt/wt %, about 2.7wt/wt %, about 2.8 wt/wt %, about 2.9 wt/wt %, about 3 wt/wt %, about3.1 wt/wt %, about 3.2 wt/wt %, about 3.3 wt/wt %, about 3.4 wt/wt %,about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt%, about 3.9 wt/wt %, about 4 wt/wt %, about 4.1 wt/wt %, about 4.2wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %,about 5 wt/wt %, about 5.1 wt/wt %, about 5.2 wt/wt %, about 5.3 wt/wt%, about 5.4 wt/wt %, about 5.5 wt/wt %, about 5.6 wt/wt %, about 5.7wt/wt %, about 5.8 wt/wt %, about 5.9 wt/wt %, about 6 wt/wt %, about6.1 wt/wt %, about 6.2 wt/wt %, about 6.3 wt/wt %, about 6.4 wt/wt %,about 6.5 wt/wt %, about 6.6 wt/wt %, about 6.7 wt/wt %, about 6.8 wt/wt%, about 6.9 wt/wt %, or about 7 wt/wt % of the crystalline compositionofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein. In some aspects, the pharmaceutical compositioncomprises about 0.5 wt/wt % of the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein. In some aspects, the pharmaceutical compositioncomprises about 0.8 wt/wt % of the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidedescribed herein.

In some aspects, the pharmaceutical composition comprises one or morediluents. In some aspects, the pharmaceutical composition comprisesabout 70 wt/wt % to about 95 wt/wt % of one or more diluents. In someaspects, the pharmaceutical composition comprises about 85 wt/wt % toabout 95 wt/wt % of one or more diluents. In some aspects, thepharmaceutical composition comprises about 70 wt/wt %, about 71 wt/wt %,about 72 wt/wt %, about 73 wt/wt %, about 74 wt/wt %, about 75 wt/wt %,about 76 wt/wt %, about 77 wt/wt %, about 78 wt/wt %, about 79 wt/wt %,about 80 wt/wt %, about 81 wt/wt %, about 82 wt/wt %, about 83 wt/wt %,about 84 wt/wt %, about 85 wt/wt %, about 86 wt/wt %, about 87 wt/wt %,about 88 wt/wt %, about 89 wt/wt %, about 90 wt/wt %, about 91 wt/wt %,about 92 wt/wt %, about 93 wt/wt %, about 94 wt/wt %, or about 95 wt/wt% of one or more diluents. In some aspects, the pharmaceuticalcomposition comprises about 90 wt/wt % of one or more diluents. In someaspects, the pharmaceutical composition comprises about 93 wt/wt % ofone or more diluents.

In some aspects, at least one of the diluents is selected from the groupconsisting of microcrystalline cellulose, lactose, mannitol, starch, anddibasic calcium phosphate. In some aspects, at least one of the diluentsis microcrystalline cellulose. In some aspects, the diluent ismicrocrystalline cellulose.

In some aspects, the pharmaceutical composition comprises about 70 wt/wt% to about 95 wt/wt % microcrystalline cellulose. In some aspects, thepharmaceutical composition comprises about 85 wt/wt % to about 95 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceuticalcomposition comprises about 70 wt/wt %, about 71 wt/wt %, about 72 wt/wt%, about 73 wt/wt %, about 74 wt/wt %, about 75 wt/wt %, about 76 wt/wt%, about 77 wt/wt %, about 78 wt/wt %, about 79 wt/wt %, about 80 wt/wt%, about 81 wt/wt %, about 82 wt/wt %, about 83 wt/wt %, about 84 wt/wt%, about 85 wt/wt %, about 86 wt/wt %, about 87 wt/wt %, about 88 wt/wt%, about 89 wt/wt %, about 90 wt/wt %, about 91 wt/wt %, about 92 wt/wt%, about 93 wt/wt %, about 94 wt/wt %, or about 95 wt/wt %microcrystalline cellulose. In some aspects, the pharmaceuticalcomposition comprises about 90 wt/wt % microcrystalline cellulose. Insome aspects, the pharmaceutical composition comprises about 93 wt/wt %microcrystalline cellulose.

In some aspects, the pharmaceutical composition comprises about 3.5wt/wt % to about 6 wt/wt % of one or more disintegrants. In someaspects, the pharmaceutical composition comprises about 3.5 wt/wt %about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt%, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about 4.6 wt/wt %, about4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, about 5 wt/wt %,about 5.1 wt/wt %, about 5.2 wt/wt %, about 5.3 wt/wt %, about 5.4 wt/wt%, about 5.5 wt/wt %, about 5.6 wt/wt %, about 5.7 wt/wt %, about 5.8wt/wt %, about 5.9 wt/wt %, or about 6.0 wt/wt % of one or moredisintegrants. In some aspects, the pharmaceutical composition comprisesabout 5 wt/wt % of one or more disintegrants.

In some aspects, at least one of the disintegrants is selected from thegroup consisting of croscarmellose sodium, sodium starch glycolate,crospovidone, and alginic acid. In some aspects, at least one of thedisintegrants is croscarmellose sodium. In some aspects, thedisintegrant is croscarmellose sodium. In some aspects, thepharmaceutical composition comprises about 3.5 wt/wt % to about 6 wt/wt% croscarmellose sodium. In some aspects, the pharmaceutical compositioncomprises about 3.5 wt/wt % about 3.6 wt/wt %, about 3.7 wt/wt %, about3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %,about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt%, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9wt/wt %, about 5 wt/wt %, about 5.1 wt/wt %, about 5.2 wt/wt %, about5.3 wt/wt %, about 5.4 wt/wt %, about 5.5 wt/wt %, about 5.6 wt/wt %,about 5.7 wt/wt %, about 5.8 wt/wt %, about 5.9 wt/wt %, or about 6.0wt/wt % croscarmellose sodium. In some aspects, the pharmaceuticalcomposition comprises about 5 wt/wt % croscarmellose sodium.

In some aspects, the pharmaceutical composition comprises 0 wt/wt % toabout 2 wt/wt % of one or more lubricants. In some aspects, thepharmaceutical composition comprises 0 wt/wt %, about 0.1 wt/wt %, about0.2 wt/wt %, about 0.3 wt/wt %, about 0.4 wt/wt %, about 0.5 wt/wt %,about 0.6 wt/wt %, about 0.7 wt/wt %, about 0.8 wt/wt %, about 0.9 wt/wt%, about 1 wt/wt %, about 1.1 wt/wt %, about 1.2 wt/wt %, about 1.3wt/wt %, about 1.4 wt/wt %, about 1.5 wt/wt %, about 1.6 wt/wt %, about1.7 wt/wt %, about 1.8 wt/wt %, about 1.9 wt/wt %, or about 2 wt/wt % ofone or more lubricants. In some aspects, the pharmaceutical compositioncomprises about 1 wt/wt % of one or more lubricants.

In some aspects, at least one of the lubricants is selected from thegroup consisting of magnesium stearate, sodium stearyl fumarate,glycerol dibehenate, and talc. In some aspects, at least one of thelubricants is magnesium stearate. In some aspects, the lubricant ismagnesium stearate. In some aspects, the pharmaceutical compositioncomprises 0 wt/wt %, about 0.1 wt/wt %, about 0.2 wt/wt %, about 0.3wt/wt %, about 0.4 wt/wt %, about 0.5 wt/wt %, about 0.6 wt/wt %, about0.7 wt/wt %, about 0.8 wt/wt %, about 0.9 wt/wt %, about 1 wt/wt %,about 1.1 wt/wt %, about 1.2 wt/wt %, about 1.3 wt/wt %, about 1.4 wt/wt%, about 1.5 wt/wt %, about 1.6 wt/wt %, about 1.7 wt/wt %, about 1.8wt/wt %, about 1.9 wt/wt %, or about 2 wt/wt % magnesium stearate. Insome aspects, the pharmaceutical composition comprises 0 wt/wt %magnesium stearate. In some aspects, the pharmaceutical compositioncomprises about 1 wt/wt % magnesium stearate.

In some aspects, the pharmaceutical composition is a capsule. In someaspects, the capsule comprises about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.25wt/wt % to about 1.5 wt/wt % of the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d)about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and (e)a gelatin capsule which encapsulates components (a)-(d).

In some aspects, the capsule comprises about 2 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.25wt/wt % to about 1.5 wt/wt % of the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d)about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and (e)a gelatin capsule which encapsulates components (a)-(d).

In some aspects, the capsule comprises about 3 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.25wt/wt % to about 1.5 wt/wt % of the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d)about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and (e)a gelatin capsule which encapsulates components (a)-(d).

In some aspects, the capsule comprises about 4 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 0.25wt/wt % to about 1.5 wt/wt % of the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; (d)about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and (e)a gelatin capsule which encapsulates components (a)-(d).

In some aspects, the capsule comprises about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt % of the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;(b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents; (c)about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants; and(d) a gelatin capsule which encapsulates components a-c.

Methods of Treatment

In some aspects, the present disclosure provides a method of treating atumor, a cancer, or a Rasopathy disorder comprising administering to asubject in need of such treatment a pharmaceutical composition describedherein.

In some aspects, the tumor is a neurofibroma. In some aspects, the tumoris a neurofibroma associated with Neurofibromatosis Type 1. In someaspects, the tumor is selected from the group consisting of cutaneousneurofibroma, plexiform neurofibroma, optic pathway glioma, low gradeglioma, high grade glioma, or malignant peripheral nerve sheath tumor.In some aspects, the tumor is plexiform neurofibroma.

In some aspects, the subject has been diagnosed with a Rasopathydisorder selected from the group consisting of neurofibromatosis type 1,neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costellosyndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome withmultiple lentigines.

In some aspects, the cancer is selected from the group consisting ofskin cancer, malignant peripheral nerve sheath cancer, leukemia,lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovariancancer, renal cancer, colorectal cancer, thyroid cancer,cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer,sarcoma, bladder cancer, head and neck cancer, endometrial cancer,esophageal cancer, adenoid cystic carcinoma, gallbladder cancer,prostate cancer, oral cancer, cervical cancer, pancreatic cancer,melanoma, hepatocellular cancer, biliary tract cancer, and serouscarcinoma of the peritoneum. In some aspects, the leukemia is selectedfrom the group consisting of acute lymphocytic leukemia, acutemyelogenous leukemia, chronic lymphocytic leukemia, and chronicmyelogenous leukemia. In some aspects, the lymphoma is selected from thegroup consisting of B-cell lymphoma, T-cell lymphoma, Burkitt'slymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinalB cell lymphoma, small lymphocytic lymphoma, and Waldenstrommacroglobulinemia. In some aspects, the lung cancer is selected from thegroup consisting of lung adenocarcinoma, squamous non-small cell lungcancer, non-squamous non-small cell lung cancer, and small cell lungcancer.

In some aspects, the subject bears a mutation or other aberration in oneor more genes for which the mutation or other aberration causes a gainor loss of function characteristic of certain cancers, wherein themutation or other aberration in one or more genes is a mutation or otheraberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1,MAP2K4, NF1, or NF2.

In some aspects, an individual dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered as more than one capsule or tablet. For example, a doseof 3 mg of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecan be administered as two capsules—one containing 2 mg and the othercontaining 1 mg or as three capsules each containing 1 mg.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 0.1 mg to about 20 mg per dose of thepharmaceutical compositions described herein. In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 0.1 mg, about 0.2 mg, about 0.3 mg,about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg,about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg,about 17 mg, about 18 mg, about 19 mg, or about 20 mg per dose. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 1 mg per dose. In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 2 mg per dose. In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 3 mg per dose. In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 4 mg per dose. In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided in an amount of about 10 mg per dose.

In some aspects, the pharmaceutical composition comprisingN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered one time, two times, three times, or four times per day.In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times per day.

In some aspects, if theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis to be administered more than one time a day, the total daily dose oftheN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecan be divided so the patient receives equal doses at eachadministration. For example, if the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis to be 4 mg administered two times per day, the patient can receive 2mg (e.g., as two 1 mg capsules) in the morning and 2 mg (e.g., as one 2mg capsule) in the evening.

In some aspects, if theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis to be administered more than one time a day, the total daily dose oftheN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamidecan be divided so the patient receives different doses at eachadministration. For example, if the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis to be 4 mg administered two times per day, the patient can receive 1mg (e.g., as one 1 mg capsule) in the morning and 3 mg (e.g., as one 1mg capsule and one 2 mg capsule) in the evening.

In some aspects, the present disclosure provides a method of treating atumor, a cancer, or a Rasopathy disorder comprising administering to apatient in need of such treatment a pharmaceutical composition describedherein, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily of about 0.1 mg to about 10 mg each.

In some aspects, the crystalline composition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered via a pharmaceutical composition described herein,wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis provided at a total daily dose that does not exceed 1 mg, 2 mg, 3 mg,4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg,15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 20 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 15 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 12 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 10 mg. Insome aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 8 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 6 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 2 mg. In someaspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 1 mg.

In some aspects, the present disclosure provides a method of treating atumor, a cancer, or a Rasopathy disorder comprising administering to apatient in need of such treatment a pharmaceutical composition describedherein, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.1 mg to about 20 mg.

In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.1 mg, about 0.2 mg,about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg,about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg,about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. Insome aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 1 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 2 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 3 mg. In some aspects, thetotal daily dose ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 4 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 5 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 6 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 7 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 8 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 9 mg. In some aspects, thetotal daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 10 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 11 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 12 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 13 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 14 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 15 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 16 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 17 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 18 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 19 mg. In some aspects,the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 20 mg.

In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily. In some aspects, the total daily doseof theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.1 mg to about 10 mgeach. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.1 mg, about 0.2 mg,about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg,about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about10 mg each. In some aspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.25 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.5 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 1 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 2 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 3 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 4 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 5 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 6 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 7 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 8 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 9 mg each. In someaspects, the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 10 mg each.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 days inwhich the total daily dose is administered; and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered. In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 consecutivedays in which the total daily dose is administered; followed by (b) 7consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 days in which the total daily dose isadministered and (ii) 2 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered. In some aspects, the ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 consecutive days in which the total dailydose is administered and (ii) 2 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;followed by (b) 7 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

In some aspects, theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising 28 days in which thetotal daily dose is administered.

In some aspects, the 28-day dosing cycle is repeated up to a total of 24consecutive 28-day dosing cycles.

In some aspects, the present disclosure provides use of a pharmaceuticalcomposition described herein for the manufacture of a medicament fortreating a cancer, a tumor, or a Rasopathy disorder.

EXAMPLES Time (minutes) 0 15 40 45 46 % mobile phase B 70 70 100 100 70

Example 1: Production of Essentially Pure Form IV

Lab Scale Production of Essentially Pure Form IV

2 kg PD-0325901 has been prepared using the below convergent synthesisscheme starting from commercially available 2,3,4-Trifluorobenzoic Acid(TFBA), 2-Fluoro-4-Iodoaniline (FIA) and chiral S-Glycerol Acetonide(SGA)

Step 1: Preparation of “Side Chain”, PD-0337792

All reactions were performed in toluene other than otherwise stated.Triflic anhydride gave the best yield.

TABLE 1 Coupling Agents for Step 1 Entry No. Coupling Agent Yield Notes1 Mesyl Chloride did not react 2 Benzyl chloride 27 Had to heat 70° C.for 166 hr 3 4-fluorobenzensulfonylchloride 27 Ran 93 hrs. at 70° C. 44-chlorobenzensulfonylchloride 35 Complete after 68 hrs. 50° C. 5 TosylChloride 36 Had to heat to 70° C. for 164 hrs 6 Benzyl chloride 52 studysolvent effects: DMF, DMSO, NMP - all similar DMSO fastest all completeafter 110 hrs., heated to 70° C. after 66 hrs. 7 Triflic anhydride 91Cooled to −74° C.

Recognizing that triflate gave the highest yield, the possibility ofeliminating the cryogenic conditions was investigated, set possibly dueto stability concerns of the “methanesulfonate” intermediate. Thefollowing experiments suggest no significant yield loss for experimentsrun at −20° C.

TABLE 2 Yield of Coupling Reaction Experimental Hold time after Yield(Alcohol to Description* TFMSA addn. IPGAP) 1.07 equiv. NHP 15 min. 85%1.07 equiv. NHP 2 hours 86% 1.77 equiv. NHP 2 hours 72% 1.07 equiv. NHP(reverse 1 hours 91% addition)* 2 g (1 eq.) SGA in 16 ml toluene was treated with triflic anhydride,trifluoromethanesulfonic acid (TFMSA) (4.2 g, 1.002 equiv.) at −20° C.and then stirred for a prescribed time prior to solidN-hydroxyphthalimide (NIP) addition or transfer to a flask containingsolid NHP.

The data presented above suggest no detrimental effect was observedafter prolonged stirring of the “trifluoromethane sulfonate”intermediate prior to the N-hydroxyphthalimide addition. Reverseaddition of intermediate mixture to solid NHP appears to give thehighest yield.

An additional advantage of the triflate usage was easy removal of theEt₃N triflate salts side product simply by water wash. This resulted inhighly pure N-hydroxyphthalimide-protected alcohol, IPGAP (PD-0333760)in Toluene, which can be isolated as crystals or carried through to thefinal deprotection reaction.

Both aqueous and anhydrous ammonia base were examined as deprotectingagents. The results were both successful. The phthalimide side productwas simply filtered out from solution of product (PD-0337792) in toluenewhen anhydrous ammonia was used. Similarly, it was filtered out from thesolution after performing azeotropic water removal from toluene whenaqueous ammonia (28% solution) was used. Anhydrous ammonia however,requires the reaction to be performed at high-pressure containment.Experiments conducted by sparging the ammonia gas gave acceptableyields; however, they required large volumes and use of a cryogeniccondenser (to avoid gas from escaping the reactor headspace).

TABLE 3 Yields for base deprotection Reagent Yield* Methyl hydrazine85-95% Anhydrous NH₃ (sparged) 78-90% Anhydrous NH₃ (50 psi) 80-92%Aqueous NH₃ 90-97% *from PD-0333760

Step 2: Fluoride Displacement

Examination of the reaction in an automated reactor reveals that thereaction is essentially dosed-controlled after the initiation period.Increasing the amount of lithium amide and increased agitation rateappear to shorten the induction time. The addition of water was shown toprolong the induction time. However, it is not clear whether it is dueto lithium hydroxide formation.

Induction time is increased when 0.1 equivalent H₂O was added. The trendwas reversed however when 0.1 equivalent lithium hydroxide was added.Induction times were decreased upon increasing lithium amide equivalentsand agitation.

CDI-assisted coupling of PD-0315209 acid and sidechain reagent followedby the acid (with aqueous HCl) hydrolysis consistently yielded goodresults in the laboratory. The development focus of this step was toensure that impurity levels are within the specification limit. Theknown impurities in the final isolated diol product are excessPD-0315209 acid, dimeric impurities and chiral impurities. The chiralimpurities are controlled by limiting the R-enantiomer in the startings-glycerol acetonide. Elevated levels of dimeric impurity (d) has beenknown to cause difficulties in the polymorph transformation step. Thedimeric impurity is formed initially by the reaction of imidazole(CDI-activated acid) in the presence of excess acid PD-0315209 formingdimer (a) and possibly (b) which are then carried through in thesubsequent IPGA coupling and acid hydrolysis steps forming dimer (c) and(d), respectively. Impurity d is referred to as PF-00191189.

The reaction can be easily carried out in the laboratory either bycharging both solids, FIPFA and CDI, followed by solvent (acetonitrile)or charging solids CDI into a slurry of FIPFA in acetonitrile. None ofthe solids is initially soluble in acetonitrile. The acid activationreaction was fast (almost instantaneous), forming highly solubleimidazolide product that turned the slurry into a clear homogenoussolution while CO₂ gas evolution occurs.

Lab experiments generally resulted in impurity levels under 3%, whichcan be completely removed by the subsequent recrystallization from a3-5% ethanol-toluene system. An additional recrystallization wasperformed in the few instances where the impurity level was above 0.3%.Table 4 shows selected results of lab experiments where elevated levelsof impurities were observed and how they were removed in the subsequentrecrystallization. The crude PD-0325901 was obtained using theacetonitrile/toluene system and the purified product was recrystallizedfrom a 5% ethanol/toluene system. Entries no. 4 and 5 used additionalsolvent to ensure impurity removal with entry 5 requiring tworecrystallizations in order to achieve a level of “ND” in the polymorphtransformation. The 8-10 ml/g crude crystallization volume was chosen tolimit product loss while maintaining a filterable slurry and ensuringremoval of impurities.

TABLE 4 Purification of PD-0325901 Tot. Imp. In Final Tot. isolated Tot.Imp. assay (after Imp. In Crude Purified polymorph Entry reaction PD-Recrystallization PD- trans- No mixture 0325901 Vol (ml/g crude) 0325901formation) 1  2.4% ND 8 ND 99.8% 2 10.5%  2% 8 ND 99.6% 3    6%  1% 8 ND99.4% 4   10% 3.2%  15 ND 98.6% 5   20% 12% 13 0.6% 98.4%*

A scale up procedure that would give tolerable levels of impuritiesprior to the polymorph transformation (<0.3%), without losing too muchproduct in the recrystallization was developed considering the solid CDIaddition rate. Fast addition is preferred to minimize impurityformation; however, the addition needs to be performed at a rate thatensures safely venting of the evolved CO₂.

A half portion of solid CDI was initially added to the PD-0325901 acid,followed by solvent addition. The remaining CDI was added then through ahopper in less than 30 minutes to ensure that the impurity levels werebelow 3%.

Polymorph Transformation

Three polymorphic forms of PD-0325901 are characterized below. Form Ihas the highest melting point (˜117° C.) and is enantiotropicallyrelated to Form IV (m.p. 112° C.), which is the more stable form belowthe estimated transition temperature of 73° C. Form II is the lowmelting form (m.p. 85° C.).

TABLE 5 Crystal Forms Melting Points and Heat of Fusions Melting Point,Heat of Fusion, DHf ° C. (J/g) Form I 117 85 Form II 90 70 Form IV 11294

Most of the polymorph transformation experiments were performed usinghighly pure PD-0325901 containing various forms and generally exhibiteda low melting point below 80° C. as the results of an efficientEtOH/Toluene recrystallization following the crude crystal isolationdirectly from the reaction mixture. These various polymorphs werecompletely dissolved in EtOH and subsequently precipitated by addingwater (20 volumes) in a 15-to-60 minute period at 20-25° C. Analysis ofthe solids sampled at less than 2 hours stirring show complete polymorphtransformation to Form IV. The only failure occurred when water wasadded almost immediately in one portion to a solution of PD-0325901 inEtOH (4 vol.). In this case, the undesired polymorph Form I was obtainedexclusively.

One anomaly in the standard procedure was observed. One lot producedmixed polymorphs but had no detectable level of impurity afterrecrystallization. The corrective procedure for this case includestransforming the low melting forms (Form II) to all Form I attemperatures close to or above 73° C. followed by a slow (˜4 h period)cooling to 20° C.

The EtOH/Water system produces an efficient polymorph transformation.The recrystallized (purified) PD-0325901, which initially consisted ofenantiotropic polymorphs Form I (m.p. ˜117° C.) and Form IV (m.p. ˜112°C.) was completely transformed to Form IV.

Pilot Plant Preparation of Essentially Pure Form IV

Step 1: Preparation of “Side Chain”, PD-0337792

14.4 kg alcohol (chemical purity 99.4%, optical purity 99.6%enantiomeric excess) was converted to 97.5 kg 9.7% w/w PD-0337792 (IPGA)solution in toluene (overall yield ˜60%). The triflate activation wasperformed in the 200 L reactor by maintaining temperatures under −20° C.during triflic anhydride addition. The resulting activated alcohol wasthen transferred to a 400 L reactor containing solid N-hydroxypthalimide(NHP) and the reaction was allowed to occur at ambient temperature tocompletion. The final base de-protection was performed by adding aqueousammonia (˜28% soln, 5 equiv., 34 kg). After reaction completion, waterwas removed by distillation from toluene, and the resulting solid sideproduct was filtered out to yield the product solution.

Step 2: Preparation of PD-0315209

The process yielded 21.4 kg (99.4% w/w assay), which is 80% oftheoretical from starting materials 2,3,4-trifluorobenzoic acid (12 kg,1 eq.) and 2-fluoro-4-iodoaniline (16.4 kg, 1.02 eq.) with lithium amidebase (5 kg, 3.2 eq.). The reaction was initiated by adding 5% of totalsolution of TFBA and FIA into lithium amide slurry at 50° C. Thisreaction demonstrated a minimal initiation period of ˜10 minutes, whichwas observed by color change and slight exotherm. The remaining TFBA/FIAsolution in THE was slowly added through a pressure can in an hour whilemaintaining the reaction temperatures within 45-55° C. There was noappreciable pressure rise (due to ammonia gas release) observed duringthe entire operation.

Step 3: Preparation of PD-0325901

A modification was made to the CDI charging to mitigate potential gasgeneration. Two equal portions of CDI were added into solid FIPFA beforeand after solvent addition (through a shot loader). The timing betweenthe two solid CDI additions (4.6 kg each) should not exceed 30 minutes.Then two intermediate filter cakes were dissolved with ethanol. Theexcess ethanol was distilled and replaced with toluene to approximately5% v/v ethanol prior to PD-0325901 recrystallization. Lab studiessuggested that the crystallization from toluene and acetonitrile andrecrystallization from ethanol in toluene would not be able to reduceimpurities which is essential for the polymorph transformation. Thepresence of a dimeric impurity (PF-00191189) at a level greater than0.2% has been known to result in the formation of undesired polymorph.

The crude crystallization from the final reaction mixture reduceddimeric impurity PF-00191189 to approximately 1.9% and the subsequentrecrystallization further reduced it to approximately 0.4%. As aconsequence, undesired polymorphs were produced. The DSC patternsindicated two different melting points ˜80° C. (low melt Form II) and˜117° C. (Form I). Also during the processing, the solids crystallizedat a much lower temperature than expected (actual ˜10° C., expected ˜40°C.). It is suspected that the unsuccessful recrystallization is due to achange in the solvent composition as a result of incomplete drying ofthe crude. Drying of the crude wet cake prior to ethanol dissolution wasstopped after about 36 hours when the crude product was ˜28 kg (26 kgtheoretical).

Polymorph Transformation

Approximately 7.4 kg of PD-0325901 (mixed polymorphs) from the finalEtOH/Water crystallization and precipitated materials from the earlierEtOH/Toluene filtrate were taken forward to the polymorphtransformation. Both crops were separately dried in the filter untilconstant weights and each was dissolved in EtOH. The combined EtOHsolution was analyzed by HPLC and resulted in an estimated amount of16.4 kg PD-0325901. The recrystallization was started after removingEtOH via vacuum distillation and adjusting the solvent composition toabout 5% EtOH in Toluene at 65° C. (i.e., EtOH is added dropwise at 65°C. until complete solids dissolution).

A slow 4-hour cooling ramp to 5° C. followed by 12 h stirring wasperformed to ensure satisfactory results. The resulting slurry wasfiltered and again it was completely dried in the filter until constantweight (approximately 3 days). The purified solid showed 99.8% purePD-0325901 with not detected level of dimeric impurity PF-00191189.

The dried solid (15.4 kg) was re-dissolved in exactly 4 volumes of EtOH(62 L) off of the filter, transferred to the reactor and precipitated bya slow (˜3 h) water addition (308 L) at 30-35° C., cooled to 20° C. andstirred for 12 h. The DSC analysis of a slurry sample taken at 2 h showsthe solids to be completely Form IV (desired polymorph).

21.4 kg PD-0315209, 9.7 kg CDI (1.05 equiv.), 91 kg solution of 9.7%PD-0337792 in Toluene (1.1 equiv.) were used and resulted in 12.74 kg ofPD-0325901 (assay 99.4%, 100% Form IV, Yield 48%).

Example 2: Assay/Impurities and Identification of PD-0325901

PD-0325901 is separated from process impurities and degradants byreversed-phase liquid chromatography with UV detection at 275 nm.Identification of PD-0325901 is performed by obtaining either aninfrared or proton NMR spectrum, in addition to the HPLC retention time.For purity evaluation, process impurities and degradants are identifiedby their characteristic relative retention times and quantitated by areanormalization.

Chromatographic Conditions: Agilent Zorbax SB C18, 5 μm, 4.6×250 mm (orequivalent); flow rate is 1.0 mL/min; column temperature is 30° C.;detector wavelength is 275 nm; diluent is 50/50 acetonitrile/water;mobile phase A is 0.1% trifluoroacetic acid (TFA) in water; mobile phaseB is methanol; and the gradient conditions below. The assay isdetermined against a reference standard and reported on an anhydrous,solvent free basis. Quantification of specified and unspecifiedimpurities is reported by area percent. Total impurities is the sum ofall impurities present above the reporting threshold of 0.05%.

Example 3: Single Crystal X-Ray Diffraction Analysis of Form IV

A suitable single crystal of Form IV was prepared by a method involvinga different coupling agent than was used in the method disclosed inExample 1. However, the crystal yielded Form IV with the same XRPDcharacteristics as Form IV prepared by the method of Example 1, and wastherefore of suitable purity for Form IV analysis.

The single Form IV crystal was analyzed using a Bruker D8 Venture PhotonII CPAD diffractometer equipped with a CuKα INCOATEC Imus micro-focussource (λ=1.54178 Å). The simulated PXRD pattern was calculated from thelow temperature (100 K) structure and room temperature (298 K, 25° C.)unit cell parameters shown below. Unit cell at room temperature wasinitially determined by Difference Vectors method based on 235reflections harvested from 151, 1° diffraction frames. Unit cellparameters were subsequently refined during data integration by Saint(Bruker (2020). SAINT. Data Reduction Software) and are based on 903reflections recorded between 19.1 and 1.1 Å resolution. The simulatedpattern was consistent with an experimental Form IV pattern as shown inFIG. 1A.

TABLE 6 Initially Determined Unit Cell Parameters at Room Temperaturea[Å] b[Å] c[Å] α[°] β[°] γ[°] V[Å3] 27.080(2) 27.080(2) 4.6971(5) 90 9090 3444.5(8)

TABLE 7 Form IV Crystal Data and Structure Refinement Crystal systemTetragonal Space group P4₁ a/Å 26.9861(4) b/Å 26.9861(4) c/Å 4.66600(10)α/° 90 β/° 90 γ/° 90 Volume/Å³ 3398.01(12) Z 8 pcalcg/cm³ 1.885 μ/mm⁻¹15.351 F(000) 1888

Example 4: Capsule Formulations

Formulation Composition 1 mg 2 mg 5 mg Ingredient % (w/w) mg/cap % (w/w)mg/cap % (w/w) mg/cap Mirdametinib ^(a) 0.77 1 0.77 2 5.26 5Microcrystalline 93.23 121.2 93.23 242.4 89.74 85.25 Cellulose ^(b)Croscarmellose 5 6.5 5 13 5 4.75 sodium Magnesium 1 1.3 1 2.6 0 0Stearate Total 100 130 100 260 100 95 Capsule Shells Size #3 Size #1Size #2 HG HG HG capsules capsules capsules HG = Hard Gelatin ^(a) Basedon a theoretical potency of 1.000. Actual quantity may be adjusted basedon the actual potency. ^(b) Quantity of microcrystalline cellulose maybe adjusted for slight potency changes of PD-0325901.

Example 5: Form IV Stability

Stability of Form IV material was determined by comparing the XRPDspectrum of a batch to a reference standard XRPD spectrum. This analysiswas performed at batch release, and the XRPD spectrum obtainedcorresponded to that of the reference standard of Form IV (FIG. 2). TheForm IV batch was then stored at 25° C. and 65% relative humidity. XRPDanalysis of the stored Form IV was performed at 68 months (FIG. 3A) andagain at 140 months (FIG. 3B). Undetectable changes in the XRPD spectraover time indicated stability of Form IV at 25° C. and ≤65% relativehumidity.

All publications, patents, and patent applications mentioned in thisspecification are incorporated herein by reference in their entirety tothe same extent as if each individual publication, patent, or patentapplication was specifically and individually indicated to beincorporated by reference in its entirety. Where a term in the presentapplication is found to be defined differently in a documentincorporated herein by reference, the definition provided herein is toserve as the definition for the term.

While the invention has been described in connection with specificaspects thereof, it will be understood that invention is capable offurther modifications and this application is intended to cover anyvariations, uses, or adaptations following, in general, the principlesand including such departures from the present disclosure that comewithin known or customary practice within the art to which the inventionpertains and can be applied to the essential features hereinbefore setforth, and follows in the scope of the claimed.

In addition to the various embodiments described herein, the presentdisclosure includes the following embodiments numbered E1 through E94.This list of embodiments is presented as an exemplary list and theapplication is not limited to these embodiments.

E1. A crystalline composition that is essentially pure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)

E2. The crystalline composition of E1, wherein the crystallinecomposition exhibits an XRPD pattern and/or DSC profile which issubstantially unchanged after storage for 3 months at standard warehouseconditions (15° C.-25° C. and ≤65% relative humidity).

E3. The crystalline composition of E1 or E2, wherein the crystallinecomposition exhibits an XRPD pattern and/or DSC profile which issubstantially unchanged after storage for 6 months at standard warehouseconditions (15° C.-25° C. and ≤65% relative humidity).

E4. The crystalline composition of any one of E1-E3, wherein thecrystalline composition exhibits an XRPD pattern and/or DSC profilewhich is substantially unchanged after storage for 1 year at standardwarehouse conditions (15° C.-25° C. and ≤65% relative humidity).

E5. The crystalline composition of any one of E1-E4, wherein thecrystalline composition exhibits an XRPD pattern and/or DSC profilewhich is substantially unchanged after storage for 68 months at standardwarehouse conditions (15° C.-25° C. and ≤65% relative humidity).

E6. The crystalline composition of any one of E1-E5, wherein thecrystalline composition exhibits an XRPD pattern and/or DSC profilewhich is substantially unchanged after storage for ≥140 months atstandard warehouse conditions (15° C.-25° C. and ≤65% relativehumidity).

E7. The crystalline composition of any one of E2-E6, wherein the XRPDpattern is generated using:

a PANALYTICAL© X'Pert Pro diffractometer using Ni-filtered Cu Kα (45kV/40 mA) radiation and a step size of 0.03° 2θ with a X'CELERATOR© RealTime Multi-Strip detector, configured

(a) on the incidental beam side as follows: variable divergence slits(10 mm irradiated length), 0.04 rad Soller slits, fixed anti-scatterslit (0.50°), and 10 mm beam mask, and

(b) on the diffracted beam side as follows: variable anti-scatter slit(10 mm observed length) and 0.04 rad Soller slit; or

a BRUKER©D8©ADVANCE™ system using Cu Kα (40 kV/40 mA) radiation and astep size of 0.030 2θ with a LYNXEYE™ detector, configured

(a) on the incidental beam side as follows: Goebel mirror, mirror exitslit (0.2 mm), 2.5° Soller slit, beam knife, and

(b) on the diffracted beam side as follows: anti-scatter slit (8 mm) and2.5° Soller slit; and

wherein samples are mounted flat on zero-background Si wafers.

E8. The crystalline composition of any one of E1-E7, wherein the DSCpattern is generated using a TA Instruments Q100 or Q2000 differentialscanning calorimeter at a rate of temperature increase of about 15°C./min.

E9. The crystalline composition of any one of E1-E8, wherein thecrystalline composition contains ≤0.2% of dimeric impurity PF-00191189.

E10. The crystalline composition of any one of E1-E9, wherein thecrystalline composition contains about 0.05% to about 0.19% by weight ofdimeric impurity PF-00191189.

E11. The crystalline composition of any one of E1-E9, wherein thecrystalline composition contains no detectable amount of dimericimpurity PF-00191189.

E12. A pharmaceutical composition comprising the crystalline compositionof any one of E1-E11 and a pharmaceutically acceptable carrier.

E13. The pharmaceutical composition of E12, wherein the pharmaceuticalcomposition is for oral administration.

E14. The pharmaceutical composition of E13, wherein the pharmaceuticalcomposition is a solid dosage form.

E15. The pharmaceutical composition of any one of E12-E14, wherein thepharmaceutical composition is a tablet or capsule.

E16. The pharmaceutical composition of E15, wherein the pharmaceuticalcomposition is a tablet.

E17. The pharmaceutical composition of E15, wherein the pharmaceuticalcomposition is a capsule.

E18. The pharmaceutical composition of E17, wherein the capsulecomprises about 1 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows:

a) about 0.25 wt/wt % to about 1.5 wt/wt % of the crystallinecomposition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;

b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents;

c) about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants;

d) about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and

e) a gelatin capsule which encapsulates components a-d.

E19. The pharmaceutical composition of E17, wherein the capsulecomprises about 2 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows:

a) about 0.25 wt/wt % to about 1.5 wt/wt % of the crystallinecomposition ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;

b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents;

c) about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants;

d) about 0.5 wt/wt % to about 2 wt/wt % of one or more lubricants; and

e) a gelatin capsule which encapsulates components a-d.

E20. The pharmaceutical composition of E17, wherein the capsulecomprises about 5 mg ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide,wherein each component of the capsule is as follows:

a) about 2.5 wt/wt % to about 7.0 wt/wt % of the crystalline compositionofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;

b) about 85 wt/wt % to about 95 wt/wt % of one or more diluents;

c) about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants;and

d) a gelatin capsule which encapsulates components a-c.

E21. The pharmaceutical composition of any one of E18-E20, wherein atleast one of the diluents is selected from the group consisting ofmicrocrystalline cellulose, lactose, mannitol, starch, and dibasiccalcium phosphate.

E22. The pharmaceutical composition of E21, wherein at least one of thediluents is microcrystalline cellulose.

E23. The pharmaceutical composition of any one of E18-E22, wherein atleast one of the disintegrants is selected from the group consisting ofcroscarmellose sodium, sodium starch glycolate, crospovidone, andalginic acid.

E24. The pharmaceutical composition of E23, wherein at least one of thedisintegrants is croscarmellose sodium.

E25. The pharmaceutical composition of any one of E18-E24, wherein atleast one of the lubricants is selected from the group consisting ofmagnesium stearate, sodium stearyl fumarate, glycerol dibehenate, andtalc.

E26. The pharmaceutical composition of E25, wherein at least one of thelubricants is magnesium stearate.

E27. A method of treating a tumor, a cancer, or a Rasopathy disordercomprising administering to a subject in need of such treatment thepharmaceutical composition of any one of E12-E26.

E28. The method of E27, wherein the tumor is a neurofibroma.

E29. The method of E28, wherein the tumor is a neurofibroma associatedwith Neurofibromatosis Type 1.

E30. The method of any one of E27-E29, wherein the tumor is selectedfrom the group consisting of cutaneous neurofibroma, plexiformneurofibroma, optic pathway glioma, low grade glioma, high grade glioma,or malignant peripheral nerve sheath tumor.

E31. The method of E30, wherein the tumor is plexiform neurofibroma.

E32. The method of E27, wherein the subject has been diagnosed with aRasopathy disorder selected from the group consisting ofneurofibromatosis type 1, neurofibromatosis type 2,cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome,Noonan syndrome, and Noonan syndrome with multiple lentigines.

E33. The method of E27, wherein the cancer is selected from the groupconsisting of skin cancer, malignant peripheral nerve sheath cancer,leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer,ovarian cancer, renal cancer, colorectal cancer, thyroid cancer,cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer,sarcoma, bladder cancer, head and neck cancer, endometrial cancer,esophageal cancer, adenoid cystic carcinoma, gallbladder cancer,prostate cancer, oral cancer, cervical cancer, pancreatic cancer,melanoma, hepatocellular cancer, biliary tract cancer, and serouscarcinoma of the peritoneum.

E34. The method of E33, wherein the leukemia is selected from the groupconsisting of acute lymphocytic leukemia, acute myelogenous leukemia,chronic lymphocytic leukemia, and chronic myelogenous leukemia.

E35. The method of E33, wherein the lymphoma is selected from the groupconsisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma,follicular lymphoma, mantle cell lymphoma, primary mediastinal B celllymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.

E36. The method of E33, wherein the lung cancer is selected from thegroup consisting of lung adenocarcinoma, squamous non-small cell lungcancer, non-squamous non-small cell lung cancer, and small cell lungcancer.

E37. The method of any one of E27-E36, wherein the subject bears amutation or other aberration in one or more genes for which the mutationor other aberration causes a gain or loss of function characteristic ofcertain cancers, wherein the mutation or other aberration in one or moregenes is a mutation or other aberration in one or more of KRAS, NRAS,HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

E38. The method of any one of E27-E37, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 20 mg.

E39. The method of any one of E27-E37, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 10 mg.

E40. The method of any one of E27-E37, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 8 mg.

E41. The method of any one of E27-E37, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 6 mg.

E42. The method of any one of E27-E41, wherein the total daily dose oftheN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily.

E43. The method of E42, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.1 mg to about 20 mg.

E44. The method of E42, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 2 mg.

E45. The method of E42, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 4 mg.

E46. The method of E42, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 6 mg.

E47. The method of E42, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 8 mg.

E48. The method of E42, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 20 mg.

E49. The method of any one of E27-E42, wherein the total daily dose oftheN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily.

E50. The method of E49, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.1 mg to about 10 mgeach.

E51. The method of E49, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 1 mg each.

E52. The method of E49, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 2 mg each.

E53. The method of E49, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 3 mg each.

E54. The method of E49, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 4 mg each.

E55. The method of E49, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 10 mg each.

E56. The method of any one of E27-E55, wherein an individual dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered as more than one capsule or tablet.

E57. The method of any one of E27-E56, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 days inwhich the total daily dose is administered; and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E58. The method of any one of E27-E56, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 consecutivedays in which the total daily dose is administered; followed by (b) 7consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E59. The method of any one of E27-E56, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 days in which the total daily dose isadministered and (ii) 2 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E60. The method of any one of E27-E56, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 consecutive days in which the total dailydose is administered and (ii) 2 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;followed by (b) 7 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E61. The method of any one of E57-E60, wherein the 28-day dosing cycleis repeated up to a total of 24 consecutive 28-day dosing cycles.

E62. Use of the pharmaceutical composition of any one of E12-E26 for themanufacture of a medicament for treating a tumor, a cancer, or aRasopathy disorder.

E63. The use of any one of E62, wherein the tumor is a neurofibroma.

E64. The use of E63, wherein the tumor is a neurofibroma associated withNeurofibromatosis Type 1.

E65. The use of any one of E62-E64, wherein the tumor is selected fromthe group consisting of cutaneous neurofibroma, plexiform neurofibroma,optic pathway glioma, low grade glioma, high grade glioma, or malignantperipheral nerve sheath tumor.

E66. The use of E65, wherein the tumor is plexiform neurofibroma.

E67. The use of E62, wherein the subject has been diagnosed with aRasopathy disorder selected from the group consisting ofneurofibromatosis type 1, neurofibromatosis type 2,cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome,Noonan syndrome, and Noonan syndrome with multiple lentigines.

E68. The use of E62, wherein the cancer is selected from the groupconsisting of skin cancer, malignant peripheral nerve sheath cancer,leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer,ovarian cancer, renal cancer, colorectal cancer, thyroid cancer,cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer,sarcoma, bladder cancer, head and neck cancer, endometrial cancer,esophageal cancer, adenoid cystic carcinoma, gallbladder cancer,prostate cancer, oral cancer, cervical cancer, pancreatic cancer,melanoma, hepatocellular cancer, biliary tract cancer, and serouscarcinoma of the peritoneum.

E69. The use of E68, wherein the leukemia is selected from the groupconsisting of acute lymphocytic leukemia, acute myelogenous leukemia,chronic lymphocytic leukemia, and chronic myelogenous leukemia.

E70. The use of E68, wherein the lymphoma is selected from the groupconsisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma,follicular lymphoma, mantle cell lymphoma, primary mediastinal B celllymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.

E71. The use of E68, wherein the lung cancer is selected from the groupconsisting of lung adenocarcinoma, squamous non-small cell lung cancer,non-squamous non-small cell lung cancer, and small cell lung cancer.

E72. The use of any one of E62-E71, wherein the subject bears a mutationor other aberration in one or more genes for which the mutation or otheraberration causes a gain or loss of function characteristic of certaincancers, wherein the mutation or other aberration in one or more genesis a mutation or other aberration in one or more of KRAS, NRAS, HRAS,BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

E73. The use of any one of E62-E72, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 20 mg.

E74. The use of any one of E62-E72, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 10 mg.

E75. The use of any one of E62-E72, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 8 mg.

E76. The use of any one of E62-E72, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered in a total daily dose that does not exceed 6 mg.

E77. The use of any one of E62-E75, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily.

E78. The use of E76, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 0.1 mg to about 20 mg.

E79. The use of E77, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 2 mg.

E80. The use of E77, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 4 mg.

E81. The use of E77, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 6 mg.

E82. The use of E77, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 8 mg.

E83. The use of E77, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered once daily at a dose of about 20 mg.

E84. The use of any one of E62-E76, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily.

E85. The use of E84, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 0.1 mg to about 10 mgeach.

E86. The use of E84, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 1 mg each.

E87. The use of E84, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 2 mg each.

E88. The use of E84, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 3 mg each.

E89. The use of E84, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 4 mg each.

E90. The use of E76, wherein the total daily dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered two times daily at a dose of about 10 mg each.

E91. The use of any one of E61-E90, wherein an individual dose of theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered as more than one capsule or tablet.

E92. The use of any one of E62-E91, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 days inwhich the total daily dose is administered; and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E93. The use of any one of E62-E91, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) 21 consecutivedays in which the total daily dose is administered; followed by (b) 7consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E94. The use of any one of E62-E91, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 days in which the total daily dose isadministered and (ii) 2 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;and (b) 7 days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E95. The use of any one of E62-E91, wherein theN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered on a 28-day dosing cycle comprising: (a) three 7-dayperiods each comprising (i) 5 consecutive days in which the total dailydose is administered and (ii) 2 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;followed by (b) 7 consecutive days in which noN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideis administered.

E96. The use of any one of E92-E95, wherein the 28-day dosing cycle isrepeated up to a total of 24 consecutive 28-day dosing cycles.

What is claimed is:
 1. A crystalline composition that is essentiallypure Form IV ofN—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamideof Formula (I)


2. The crystalline composition of claim 1, wherein the crystallinecomposition exhibits an XRPD pattern and/or DSC profile which issubstantially unchanged after storage for 3 months at standard warehouseconditions (15° C.-25° C. and ≤65% relative humidity).
 3. Thecrystalline composition of claim 1, wherein the crystalline compositioncontains ≤0.2% by weight of dimeric impurity PF-00191189.


4. The crystalline composition of claim 3, wherein the crystallinecomposition contains about 0.05% to about 0.19% by weight of dimericimpurity PF-00191189.
 5. The crystalline composition of claim 1, whereinthe crystalline composition contains no detectable amount of dimericimpurity PF-00191189.
 6. A pharmaceutical composition comprising thecrystalline composition of claim 1 and a pharmaceutically acceptablecarrier.
 7. The pharmaceutical composition of claim 6, wherein thepharmaceutical composition is for oral administration.
 8. Thepharmaceutical composition of claim 6, wherein the pharmaceuticalcomposition is a tablet or capsule.
 9. The pharmaceutical composition ofclaim 8, wherein the pharmaceutical composition is a tablet.
 10. Thepharmaceutical composition of claim 8, wherein the pharmaceuticalcomposition is a capsule.